Very Long Chain Acyl-CoA Dehydrogenase Deficiency

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an autosomal recessive fatty acid oxidation disorder caused by ACADVL variants (17p13.1), which impairs the first step of beta oxidation of long chain (C14 to C20) fatty acids in the mitochondria, particularly affecting the heart, liver and skeletal muscle. Incidence is about 1 in 40,000 to 120,000.

Phenotypes: severe early onset (cardiomyopathy, hepatic and multiorgan failure in neonates and infants), intermediate (childhood hypoketotic hypoglycaemia), and late onset myopathic (exercise induced rhabdomyolysis in adolescents and adults).

• Severe neonatal form: hypertrophic or dilated cardiomyopathy, arrhythmias, pericardial effusion, hepatomegaly, hypoglycaemia, hypotonia, lactic acidosis, and high early mortality (up to about 75% in the cardiac phenotype before treatment)
• Hepatic form (infancy to childhood): recurrent episodes of hypoketotic hypoglycaemia triggered by fasting or illness, hepatomegaly, liver dysfunction
• Myopathic form: exercise or fasting induced myalgia, muscle weakness, rhabdomyolysis with myoglobinuria and acute kidney injury, triggered by prolonged exercise, cold, fasting, or infection; also pregnancy and anaesthesia
• Retinitis pigmentosa and neuropathy (more with LCHAD and TFP deficiency than VLCAD)
• Between episodes the patient may be asymptomatic

1. Newborn screening acylcarnitine profile: elevated C14:1 (tetradecenoylcarnitine, the hallmark), C14, C14:2, C12:1 (C14:1/C2 ratio).
2. Confirm with plasma acylcarnitines (C14:1, C14:2, C12:1, C16 and C18:1 with low free carnitine), ACADVL gene sequencing, and VLCAD enzyme activity or palmitoyl-CoA oxidation in lymphocytes or fibroblasts (typically below 20% of normal in severe disease).
3. During acute events: creatine kinase (markedly elevated, above 10,000 IU/L in rhabdomyolysis), glucose, lactate, ammonia, liver function tests, uric acid, urinary myoglobin, troponin, and ECG and echocardiogram for cardiac involvement.
4. Exclude other disorders: LCHAD, TFP, carnitine palmitoyltransferase II and carnitine acylcarnitine translocase deficiencies, which have overlapping acylcarnitine profiles.

• Fasting avoidance: infants require frequent feeds (every 3 to 4 hours), with overnight uncooked cornstarch (1 to 2 g/kg) or continuous nasogastric feeds if hypoglycaemia occurs; older children can fast up to 6 to 12 hours depending on severity and age.
• Dietary fat modification: restrict long chain fat to about 25% of energy (10 to 20% in severe forms) with supplementation of medium chain triglycerides (MCT oil; 20 to 25% of energy in infants and 1 to 2 g/kg/day for older children) as an alternative fuel, plus essential fatty acids (linoleic and alpha linolenic acid, as walnut or flaxseed oil or fish oil, to prevent deficiency, 1 to 2% of energy) and fat soluble vitamins. Monitor for diarrhoea and abdominal discomfort with MCT. MCT is contraindicated in disorders of ketone body or medium chain oxidation (like MCAD).
• Triheptanoin (odd chain C7 triglyceride; 25 to 35% of total daily calories, in 4 divided doses) is approved for long chain fatty acid oxidation disorders; improves cardiac function, hypoglycaemia and rhabdomyolysis episodes in some patients, with gastrointestinal adverse effects; used in severe disease and rhabdomyolysis.
• Sick day management: for fever, gastroenteritis or decompensation, give a high carbohydrate emergency regimen, with early hospital admission for IV 10% dextrose (glucose infusion rate 8 to 10 mg/kg/min), and avoid lipid infusions (including propofol).
• Exercise: avoid prolonged exercise without carbohydrate; take 0.5 to 1 g/kg of glucose polymer or 0.3 g/kg MCT oil before moderate exercise, and keep well hydrated.
• Acute rhabdomyolysis: vigorous hydration (isotonic saline 1.5 to 2 times maintenance, aiming for urine output above 2 to 3 mL/kg/hour), dextrose, electrolyte monitoring (potassium, calcium and phosphate), alkalinisation where indicated, and renal replacement if needed.
• Cardiomyopathy: standard heart failure therapy, arrhythmia control, and avoid dehydrating or catabolic triggers; carnitine supplementation is not recommended routinely because of long chain acylcarnitine toxicity (arrhythmogenic).
• Long term monitoring: growth, cardiac function (echocardiography and ECG annually), creatine kinase, liver function, and dietitian review.
• Genetic counselling: 25% recurrence risk, with testing of siblings and prenatal diagnosis.